Cytoreductive surgery has been used as adjuvant treatment for cancer patients whose tumor is believed to be too extensive for cure by either drugs or surgery alone. Accelerated growth of metastases following surgical excision or debulking of a primary tumor is a recognized clinical problem, and has been noted, in particular, in osteogenic sarcoma and testicular cancer.
The phenomenon of accelerated growth of metastases has been attributed to release of viable cells resulting from the manipulation of the tumor during surgery, or to acceleration of growth of metastases which originates before surgery on the tumor occurred. Accelerated growth of presurgical metastases has been attributed to changes in the immune status of the host secondary to removal of a major portion of the tumor or to other direct or indirect effects of the surgical procedure. It has been postulated that microscopic tumor remaining after surgery is able to grow more rapidly than is the primary tumor because the former is not subjected to factors restricting its growth, e.g., anatomical boundaries, anoxia, and nutritional deficiencies.
Enhanced growth of metastases following partial excision of implanted tumors in mice was first reported by Marie and Clunet in 1910, and by Tyzzer in 1913. These workers stated that partial removal of implanted tumors made available larger supplies of some "nutritive substances" to enhance the growth of metastases. This theory was a modification of Ehrlich's hypothesis that an actively growing tumor removed certain specific growth substances from a host animal.
More recently, Simpson-Herren et al. Cancer Treat. Rep. 60:1749 (1976)! described a study in which a surgical procedure which was designed to simulate tumor excision but which left both the primary tumor and its spontaneous metastases undisturbed (a sham procedure) resulted in a slight increase in the thymidine index of Lewis lung tumor pulmonary metastases, and a decrease in the animals' lifespans.
Other investigators have reported similar enhanced growth of metastases as a result of surgical or non-surgical trauma or stress. Of particular note, Fisher et al. Cancer Res. 49:1996 (1989)! evaluated the effect of removal of a primary tumor on the kinetics of cells in the metastasis of six different tumors. They found an increase in the labelling index of distant tumor focus (metastasis) associated with the removal of each of the tumor types. Serum, obtained from mice following removal of a tumor, when transferred to a mouse-recipients with the same type of tumor, resulted in an increase in the labelling index of the recipients' tumors. However, if the serum was obtained less than 18 hours after surgery, or if the mice with tumors were not subjected to surgery, then the serum failed to augment substantially the labelling index of tumors in mouserecipients. These investigators concluded that their results refute the premise that removal of a primary tumor is a local phenomenon with no biological consequences.
Alexander et al. Adv. Exp. Med. Biol. 233:345 (1988)! studied the phenomenon of preferential growth of blood-borne cancer cells at sites of trauma, and concluded that while several factors contribute to making a wound a more favorable growth environment for metastases, a major mechanism is the release of growth factors from macrophages which have infiltrated the wound.
Adenocarcinoma of the prostate gland is a common malignancy with an incidence that rapidly rises with age after 50. It is the single most common site of cancer in males over 70. Despite advances in surgical and medical therapy for carcinoma of the prostate, this malignancy continues to be a leading cause of cancer-related death in American men. During the last 30 years, the mortality rate from prostate cancer has remained essentially unchanged.
There are a number of similarities between benign prostatic hyperplasia (BPH) and cancer. Although no casual relationship has been found between BPH and prostate cancer, there are a number of compelling similarities, including increasing incidence and prevalence with age, concordant natural history, and hormonal requirements for growth and development.
Although patients with localized disease are often asymptomatic, localized advanced disease can be accompanied by symptoms of bladder outlet obstruction requiring therapeutic surgical intervention. Benign outlet obstruction from central prostatic hypertrophy is also common, requiring transurethral resection of the prostate (TURP).
Prostatectomy for benign disease is a misnomer. Regardless of the type of prostatectomy performed for benign obstructive disease (suprapubic, retropubic, perineal or transurethral), the prostate is not removed. A variable but substantial thickness of glandular prostatic tissue remains after removal of an adenomatous enlargement of the periurethral glands. Cancer can and does develop in the remaining prostatic tissues.
Early diagnosis of carcinoma of the prostate is hindered by the lack of symptoms in men with localized tumors. Whereas most studies of prostate cancer screening have been conducted in asymptomatic men, others have dealt with screening of men before prostatectomy for presumed benign glandular involvement. Of particular importance, therefore, is that pathologic evidence of clinically occult cancer is found in 10% to 20% of men undergoing surgery for BPH. See Denton, S. E. et al. J. Urol. 93:296 (1965); Sheldon, C. A. et al. J. Urol 124:626 (1980).
Stage A carcinoma of the prostate has been defined as cancer found at autopsy incidentally and in pathologic sections of resected glands believed preoperatively to have been benign. Whitmore, W. F., Jr., Amer. J. Med. 21:697 (1956). Autopsy studies indicate that the incidence of such cases is 25% to 30% in men who were &gt;50 years old. Hudson, P. B. et al., J.A.M.A. 155:426 (1954).
That surgical trauma may trigger these latent cancer cells into increased proliferation and/or metastasis is indicated by the following clinical examples. Armenian, et al. Armenian, H. K. et al., Lancet 2:115-117, 1974! obtained follow-up on 611 patients up to 18 years after TURP and open prostatectomy, and found a significantly greater frequency of cancer in those with BPH (11.4%) compared with controls without BPH (3.2%). The death rate for prostate cancer was 3.7 times higher among patients with BPH than among controls. The authors also retrospectively compared 290 cancer patients with age-matched controls, and noticed a relative risk of 5.1 for prostate cancer in patients treated for BPH.
A study done by Hanks, et al. J. Urol. U 129:309 (1983)! on 443 patients treated with radiation therapy for cancer of the prostate, compared survival of patients whose cancer was diagnosed by TURP to those diagnosed by needle biopsy, a significantly less traumatic procedure. This analysis indicated a doubling of recurrence and of deaths of patients diagnosed by TURP.
McGowan Int. J. Radiat. Oncol. Biol. Phys. 6:1121 (1980)! reported a retrospective study of 291 patients treated with definitive radiotherapy at the Cross Cancer Institute of Edmonton. Actuarial disease-free survival and survival corrected for intercurrent death were determined for each stage and by method of diagnosis. A significant difference in 5-year disease-free survival for Stages B and C was demonstrated: 72% and 51% for needle versus TURP, respectively (p=0.005 by Gehan's Wilcoxon two-sided test).
The literature is replete with clinical examples illustrating the poorer prognosis and shorter survival of prostate cancer patients subjected to the more surgical trauma of TURP as compared to needle biopsy.
A surgical procedure which is gaining in popularity for the treatment of early breast cancer is "lumpectomy". Although lumpectomy is not a traumatic as mastectomy, it is a surgical procedure which does not explore, or remove, the draining lymph nodes which may contain residual cancer cells. Lumpectomy is relatively new on the surgical scene, and does not have the repertoire of clinical studies illustrating the effects of surgical trauma on tumor recurrence and survival. However, a parallelism with the prostate is likely.
Wide margin surgical excision is the first therapeutic modality applied to the treatment of primary cutaneous malignant melanoma. Depending upon the degree of local infiltration or involvement of the draining lymph nodes, surgery may be followed with radiation and/or chemotherapy. However, recurrence of tiny melanotic lesions at the surgical site or along the draining lymph channels are clinically readily recognized and a common indication of progressive disease. Because of the difficulty in treating advanced malignant melanoma, ethical considerations have not permitted clinical studies comparing survival or metastatic spread of cutaneous malignant melanoma in patients subjected or not subjected to surgical excision of the primary cutaneous lesion.
It has recently been reported that a somatostatin analog inhibits growth but not wound healing. See Abribat T. et al. Endocrine Society, 74th Annual Meeting, Abstract #1384 (1992).